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Magnesium as a conformational gatekeeper of KRAS: Structural dynamics and therapeutic implications.

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Τίτλος: Magnesium as a conformational gatekeeper of KRAS: Structural dynamics and therapeutic implications.
Συγγραφείς: Srinivasu BY; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA., Damerla TS; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA., Stec A; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA., Zhou Z; Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.; Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA., Engen JR; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA., Westover KD; Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.; Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA., Wales TE; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
Πηγή: Protein science : a publication of the Protein Society [Protein Sci] 2026 Jul; Vol. 35 (7), pp. e70681.
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
Imprint Name(s): Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
Ιατρικοί όροι (MeSH): Proto-Oncogene Proteins p21(ras)*/chemistry , Proto-Oncogene Proteins p21(ras)*/metabolism , Proto-Oncogene Proteins p21(ras)*/genetics , Magnesium*/chemistry , Magnesium*/metabolism , SOS1 Protein*/chemistry , SOS1 Protein*/metabolism , SOS1 Protein*/genetics, Guanosine Triphosphate/metabolism ; Guanosine Triphosphate/chemistry ; Guanosine Diphosphate/metabolism ; Guanosine Diphosphate/chemistry ; Humans ; Protein Conformation ; Hydrogen Deuterium Exchange-Mass Spectrometry
Περίληψη: Magnesium serves as an essential cofactor for small GTPases, yet its structural role in regulating KRAS conformational dynamics and nucleotide exchange remains poorly understood. Here, we combine hydrogen-deuterium exchange mass spectrometry (HDX-MS), native mass spectrometry, and functional assays to elucidate how Mg2+ stabilizes the KRAS conformational ensemble and constrains transitions between GDP- and GTP-bound states. Depletion of Mg2+ triggers widespread increases in structural dynamics throughout KRAS-spanning the p-loop, α1-helix, switch I, nucleotide-binding region, and distal helices-revealing a global loosening of the protein fold that favors an open, nucleotide exchange-competent state. Mg2+ titration experiments demonstrate that individual structural elements exhibit distinct Mg2+ dependencies: the p-loop and α1-helix recover native dynamics at micromolar concentrations, whereas switch I requires millimolar levels, underscoring its exceptionally high sensitivity to Mg2+ for structural stabilization. KRAS bound to the catalytic domain of exchange factor SOS1 displays an HDX signature closely resembling the Mg2+-free state, indicating that SOS1 promotes nucleotide exchange by transiently perturbing Mg2+ coordination while simultaneously stabilizing switch I. Consistently, the phosphomimetic KRAS S17E variant, which disrupts a critical Mg2+-coordinating residue, exhibits pronounced global destabilization-reinforcing the central importance of Mg2+ in maintaining structural integrity. Taken together, our findings show that Mg2+ acts as a master regulator of KRAS structural dynamics and reveal Mg2+-sensitive hotspots that might represent promising targets for next-generation KRAS therapeutics.
(© 2026 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
Σχόλια: Update of: bioRxiv. 2026 Feb 23:2026.02.20.707046. doi: 10.64898/2026.02.20.707046.. (PMID: 42124585)
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Grant Information: NIH R01CA244341 United States NH NIH HHS; R01 CA233978 United States CA NCI NIH HHS; K01 CA313805 United States CA NCI NIH HHS; CPRIT RP220145 United States NH NIH HHS; R01 CA244341 United States CA NCI NIH HHS; R01CA233978 United States NH NIH HHS
Contributed Indexing: Keywords: HDX‐MS; KRAS; SOS1; allostery; hydrogen/deuterium exchange mass spectrometry; magnesium
Substance Nomenclature: EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
I38ZP9992A (Magnesium)
0 (KRAS protein, human)
0 (SOS1 Protein)
0 (SOS1 protein, human)
86-01-1 (Guanosine Triphosphate)
146-91-8 (Guanosine Diphosphate)
Entry Date(s): Date Created: 20260618 Date Completed: 20260618 Latest Revision: 20260927
Update Code: 20260927
PubMed Central ID: PMC13278026
DOI: 10.1002/pro.70681
PMID: 42313706
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1469-896X
DOI:10.1002/pro.70681